Heterocycles [h]-Fused onto 4-Oxoquinoline-3-carboxylic Acid, III. Facile Synthesis and Antitumor Activity of Model Heterocycles [a]-Fused onto Pyrido[2,3-f]quinoxaline-3-carboxylic Acids
2007
Direct interaction between 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and each of (S)-proline, (2S,4R)-4-hydroxyproline and (5)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid in hot aqueous ethanolic NaHCO 3 yielded the corresponding optically pure N-(4-oxoquinolin-7-yl)-α-amino acids. The latter derivatives underwent reductive lactamization upon treatment with Na 2 S 2 O 4 in aqueous ethanol to afford moderate yields of the respective pyrido[2,3-/]quinoxaline-3-carboxylic acid [fused]- to tetrahydropyrrolo[1,2-a]-, tetrahydrohydroxylpyrrolo[1,2-a]-and tetrahydroisoquin-olino[2,3-a]heterocyclics 10-12, respectively. The antitumor activity against four human tumor cell lines showed that 10-12 displayed high levels of cytotoxicity as compared with Cisplatin. Interestingly, these compounds were more potent against breast carcinoma cell lines (MCF-7 and T-47D) than the lymphoid origin tumor cell lines (Jurkat and BHL-89). In particular, the (S)-proline derivative 10 exhibited preferential cytotoxicity to adherent cells (IC 50 = 0.5 μM), indicative of better potential in blocking the growth of solid tumors rather than the disseminated ones.
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